Drugs of abuse are known to be a significant co-factor in HIV infection. However addressing whether drugs of abuse are significant co-factors in disease progression has been difficult. Methamphetamine (METH) is a frequently and increasingly used drug among those infected with HIV, and those at high risk for becoming HIV infected. Our Preliminary Data indicates that METH can negatively affect many parameters of simian immunodeficiency virus (SIV)-induced disease in monkeys. Here we proposed a well- powered study to obtain definitive results on the interaction of METH and SIV. Our hypothesis is that there are distinct areas of interaction occur between these agents that combine to increase disease. First, there is a combined toxic effect in the central nervous system (CNS), in which SIV and METH combine to yield functional and biochemical deficits both greater and different than either agent alone. Second, there is an interaction in the immune system that affects disease course and likely secondarily the CNS. Third, both SIV and METH affect autophagy, an essential process in neurons whose disruption leads to neuronal damage, and the effects of SIV and METH together are greater than either alone. Pharmacological agents that affect autophagy will be tested in a preclinical setting to provide both mechanistic insights and provide leads for treatment strategies. Those infected with HIV, and those at high risk for HIV infection, include people that frequently use drugs of abuse, including methamphetamine, the use of which is increasing nationwide. Methamphetamine can damage the brain, as can HIV infection. Here we will examine how these two agents interact to cause brain as well as other problems, and such work will provide insight into not only these two agents, but means to protect neurons from other damaging processes.